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By broadly comparing the DNA of children to that of elderly people, gene researchers at The Children's Hospital of Philadelphia have identified gene variants that influence lifespan, either by raising disease risk or by providing protection from disease.

"This research is the first genome-wide, population-based study of copy number variations in children associated with human longevity," said Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. Dr. Hakonarson led the study which appeared recently in PLOS ONE.

Copy number variations (CNVs) are losses or gains in DNA sequence that are usually rare, but which can play an important role in raising or lowering the risk of disease. The study team compared the rates of CNVs in a sample of 7,313 young subjects, 18 years old and below, from the Children's Hospital network, to a group of 2,701 Icelandic subjects, 67 years old or above, recruited by the Icelandic Heart Association. The researchers used microchip arrays to perform the whole-genome CNV analyses.

After performing a replication study in an independent U.S. cohort of 2,079 children and 4,692 older people and making statistical adjustments to address population stratification, the study team found seven significant CNVs. Three of the CNVs were deletions of DNA sequence, while four were duplications.

The genes impacted by the CNVs were disproportionately involved in alternative splicing. This is an important biological mechanism in which, instead of one gene simply expressing one protein, modifications to messenger RNA result in different protein products based on the same underlying DNA code in a given gene.

Although much work remains to be done, Dr. Hakonarson said that the CNVs overrepresented in children may represent novel targets implicated in short lifespan. Eventually, if such CNVs are incorporated into early clinical screening tests, their presence could be prognostic markers indicating which patients should take individualized preventive health measures, Dr. Hakonarson noted.